Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.
Ionization and structural properties of mRNA lipid nanoparticles influence expression in intramuscular and intravascular administration.
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DOI：
10.1038/s42003-021-02441-2
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发表时间：
2021-08-11
影响因子：
5.9
通讯作者：
Buschmann MD
中科院分区：
文献类型：
--
作者：
Carrasco MJ;Alishetty S;Alameh MG;Said H;Wright L;Paige M;Soliman O;Weissman D;Cleveland TE 4th;Grishaev A;Buschmann MD
脂质纳米颗粒（LNPs）用于递送siRNA和COVID-19 mRNA疫苗。已知决定其递送效率的主要因素是LNP中含有可电离脂质的pKa。本文报道了一种从可电离脂质结构预测LNP pKa的方法。我们使用理论、核磁共振、荧光染料结合和电泳迁移率方法来全面测量可电离脂质和配方LNP的质子化。可电离脂质的pKa比LNP的pKa高2-3个单位，这主要是由于LNP和水介质之间质子溶剂化能的差异。我们利用这些结果来解释不同的可电离脂质在LNP中以不断升高的可电离脂质与mrna的比率在肌内和血管内给药的体内和体外递送效率。此外，我们确定在IM给药后，更多带负电荷的LNPs在肝脏中表现出更高的脱靶全身mRNA表达。通过适当设计可电离脂质和LNP，可以最大限度地减少mRNA-LNP疫苗的系统性脱靶表达。Carrasco等人报道了一种可以从可电离脂质结构预测脂质纳米颗粒（LNP） pKa的方法。他们研究了肌内和血管内给药的递送效率，并提出了限制mRNA LNP疫苗脱靶全身分布和表达的设计原则。
Lipid Nanoparticles (LNPs) are used to deliver siRNA and COVID-19 mRNA vaccines. The main factor known to determine their delivery efficiency is the pKa of the LNP containing an ionizable lipid. Herein, we report a method that can predict the LNP pKa from the structure of the ionizable lipid. We used theoretical, NMR, fluorescent-dye binding, and electrophoretic mobility methods to comprehensively measure protonation of both the ionizable lipid and the formulated LNP. The pKa of the ionizable lipid was 2-3 units higher than the pKa of the LNP primarily due to proton solvation energy differences between the LNP and aqueous medium. We exploited these results to explain a wide range of delivery efficiencies in vitro and in vivo for intramuscular (IM) and intravascular (IV) administration of different ionizable lipids at escalating ionizable lipid-to-mRNA ratios in the LNP. In addition, we determined that more negatively charged LNPs exhibit higher off-target systemic expression of mRNA in the liver following IM administration. This undesirable systemic off-target expression of mRNA-LNP vaccines could be minimized through appropriate design of the ionizable lipid and LNP. Carrasco et al. report a method that can predict the lipid nanoparticles (LNP) pKa from the structure of the ionizable lipid. They investigate the delivery efficiency for intramuscular and intravascular administration and propose design principles to limit off-target systemic distribution and expression for mRNA LNP vaccines.
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